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The descriptions above provide a concise insight into the complex regulation of GSH synthesis.As mentioned above, the synthesis of GSH is also Oxytetracycline dependent upon the availability of the rate limiting amino acid cysteine.In neuronal tissue, cells must take up a majority of the cysteine they use in GSH production from the extracellular space.Cysteine incorporation into neurons and astrocytes occurs via two primary mechanisms.First, neurons primarily use excitatory amino acid transporters to bring cysteine into cells. Secondly, astrocytes use the cystineglutamate transporter to increase intracellular levels of cysteine through the uptake of cysteine, the oxidized fo rm of cysteine.In addition to importation of extracellular cyst ine, cells can generate cysteine using intracellular polypeptides as precursors in a process called transsulfuration.However, the relative importance of uptake mechanisms and transsulfuration is celltype dependent, as described briefly below for the specific brain cell types, along with references to more indepth discussions.Astrocytes are reported to have higher GSH levels than neurons and also to have the ability to secrete GSH into the extracellular space. This secretion of GSH serves as a precursor supplier for other brain cells.Additionally, GGT can transfer the glutamyl moiety to an amino acid acceptor; one of these acceptors is cystine. The resulting glutamylcystine has been shown to increase GSH content in vivo, as mice injected with radiolabeled glutamylcystine showed almost a doubling of kidney GSH levels. A more recent study using primary astrocytes also investigated the mechanism of glutamylcystine uptake.However, this study found that pretreatment of the astrocytes with Venlafaxine hydrochloride acivicin resulted in no change in intracellular GSH levels compared to control cells treated with cystine in the absence of acivicin. The basic routes of synthesis of GSH in astrocytes and neurons within the brain are depicted diagrammatically.This reaction occurs in both astrocytes and neurons.Direct uptake of GSH across the blood brain barrier and into brain cells has been suggested, but it is unlikely that such direct uptake contributes in a quantitatively important way to the GSH concentration in brain cells. The EAAT system is responsible for about of total cysteine uptake in neurons, whereas cystine does not serve as a source for neuronal GSH synthesis. Approximately of EAAC is located at the plasma membrane during basal conditions, but during times of stress EAAC translocates to the plasma membrane. EAAC expression can be modulated by a variety of factors including serum and glucocorticoidinducible kinase, phosphoinositidedependent kinase, and GTRAP. The importance of EAAC to support induction of GSH synthesis and cellular viability has been investigated recently.Additionally, knockdown of EAAC or increased expression of GTRAP lead to increased DNA fragmentation when in HEKT cells treated with HO. Demonstrating the importance of EAAC in neuronal cells, in vitro partial knockdown of EAAC in primary neurons resulted in decrease in cysteine uptake and a increase in cell death when these altered neurons were treated with HO. Furthermore, in vivo embryonic knockout of EAAC showed age dependent neurodegeneration and significant loss of GSH content. In astrocytes the primary precursor imported into the cell for GSH production is cystine.

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